Human malaria caused by Plasmodium parasites strikes over 200 million people a year, leading to ~1 million deaths a year. This disease is particularly damaging to children, with one child one every minute succumbing to the disease in Africa (World Health Organization). Glucose metabolism is critical to the success of the intra- erthyrocytic disease-causing lifecycle stages of the P. falciparum, the most virulent species of the parasite. The goal of this application is to identify inhibitor probes of the first enzyme in glycolysis in the parasie, P. falciparum hexokinase (PfHK), through a high throughput screening campaign in collaboration with the NIH National Center for Advancing Translational Sciences (NCATS). We will systematically confirm the inhibitory activity of primary hits using a series of standardized secondary confirmation assays with hits being scored for anti-parasitic activity. Through an iterative approach that weighs activity against enzyme and parasite based on structural modifications, a probe will be identified that is a potent inhibitor of PfHK with promising anti- malarial activity.
The proposed research is important to public health as identification of novel inhibitors of the Plasmodium falciparum hexokinase with anti-parasitic activity will serve as the first step in the development of desperately needed therapeutics for human malaria, a disease that devastates communities throughout the world, particularly through the disease it causes in children. Additionally, the identification of a probe inhibitor wil allow us to further our understanding of the fundamental cellular roles of the PfHK in parasite biology, topics that are supported by the mission of the NIH.